Maackiain protects against sepsis via activating AMPK/Nrf2/HO-1 pathway

Sepsis is a life-threatening medical condition caused by infection-triggered aberrant immune responses, leading to host tissue and organ injury. Despite advances in medical interventions, the mortality rate for septic shock remains high. Recent studies highlight the role of oxidative stress in the occurrence and development of sepsis, providing a potential therapeutic target for preventing sepsis-associated organ injury. In this study, we showed that Maackiain, a natural compound isolated from Sophora flavescens, exerted a protective role in a cecal ligation and puncture (CLP)-induced murine model of sepsis. Maackiain treatment reduced organ injury, and mitigated systematic inflammation and oxidative stress in septic mice. Maackiain also reduced the levels of inflammatory cytokines and reactive oxygen species (ROS) in RAW264.7 macrophage cells stimulated with lipopolysaccharide (LPS). We further demonstrated that Maackiain initiated activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in RAW264.7 cells in an AMP-activated protein kinase (AMPK)-dependent way. Moreover, inhibition of AMPK/Nrf2 axis abrogated the anti-inflammatory and anti-oxidant effects of Maackiain both in vitro and in vivo. Collectively, our study indicates that Maackiain treatment inhibits inflammatory response and oxidative stress via activation of AMPK/Nrf2/HO-1 pathway, thus exerting a protective effect against sepsis, providing an alternative option for sepsis prevention.